WO 02/50051 discloses the compound 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-1′-phenyl-1′-[N′-(carboxymethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine (elobixibat; IUPAC name: N-{(2R)-2-[({[3,3-dibutyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl]oxy}acetyl)amino]-2-phenyl-ethanolyl}glycine). This compound is an ileal bile acid transporter (IBAT) inhibitor, which can be used in the treatment or prevention of diseases such as dyslipidemia, constipation, diabetes and liver diseases. According to the experimental section of WO 02/50051, the last synthetic step in the preparation of elobixibat consists of the hydrolysis of a tert-butoxyl ester under acidic conditions. The crude compound was obtained by evaporation of the reaction mixture under reduced pressure and purification of the residue by preparative HPLC using acetonitrile/ammonium acetate buffer (50:50) as eluent (Example 43). After freeze drying the product, no crystalline material was identified.
It would be desirable to discover a form of elobixibat that is sufficiently robust to be suitable for formulation as a pharmaceutical.
During crystallization studies that form the basis for this invention, it was observed using X-ray powder diffraction (XRPD) techniques that elobixibat crystallized from many solvents or mixtures of solvents by incorporating solvent molecules in its structure, thereby forming specific solvates or mixed solvates. Thus, different crystal modifications of elobixibat were obtained in many solvents or combinations of solvents. Different crystal modifications were even obtained when the same solvent was used. Further, using thermal gravimetric analysis (TGA), it was concluded that different samples of the same crystal modification may contain different amounts of solvents. Additional crystal modifications of elobixibat were obtained when the incorporated organic solvent molecules were evaporated from the crystallized solvates. Thus, the experimental work supporting the present application found that many crystal modifications of elobixibat were unstable, and/or were observed to transform into other crystal modifications. It was therefore difficult to obtain consistent results by repeating similar experiments.
Different solvated crystal modifications may be revealed by using a very fast X-ray detector and withdrawing a wet sample from a slurry of the solid material to be analyzed onto a sample holder, keeping the sample at the experiment temperature and then analysing the sample quickly and repeatedly as it dries. This technique can show an initially formed solvate or mixed solvate, the desolvated modification or a mixture of the two. If more than one partially or completely desolvated crystal modification exists, there are even more possible variations of XRPD-data. It was thus a further challenge just to obtain XRPD-data for a pure crystal modification.
Various crystal modifications may have disadvantages including a variable degree of crystallinity and difficulties in handling and formulating. Thus, there is a need for stable crystal modifications of elobixibat having improved properties with respect to stability, bulk handling and solubility. It is therefore an object of the present invention to provide a stable and highly crystalline crystal modification of elobixibat.